1. Field of the Invention
The invention relates to polypeptides containing a cytoplasmic domain ending with a MAST-2 binding domain, the first two residues of which are S and W, and the last four residues of which are Q, T, R and L, said polypeptides presenting a high affinity for the PDZ domain of the human MAST2 protein. The invention also relates to polynucleotides, vectors, lentiviral particles, cells as well as compositions comprising the same. The invention is also directed to the use of said polypeptides, polynucleotides, vectors, lentiviral particles, cells and compositions in the treatment and/or prevention of a disease, disorder or condition, which alters the Central Nervous System (CNS) and/or the Peripheral Nervous System (PNS). The invention also concerns molecular signatures of cellular genes to determine the neurosurvival and/or neuroprotection activity of a molecule.
2. Description of Related Art
During development of the nervous system, neurons extend axons over considerable distances in order to innervate their targets in an appropriate manner. This involves the stimulation in the cells of specific signaling pathways which can stimulate the activity of the growth cone.
While the developing nervous system, more particularly the developing central nervous system, is highly plastic, the adult nervous system, more particularly the adult brain, has more limited repair potential. Therefore, neurite-axon outgrowth and protection against degeneration are important factors to be considered to improve the outcome of a neurodegenerative disease, disorder or condition, such as an acute injury of the nervous system or a chronic neurodegenerative disorder. Products, which would be capable of inducing neurite outgrowth from such neuronal cells, would bring a very useful therapeutic and/or preventive and/or palliative solution to such diseases, disorders or conditions.
At the other side of the neuron developmental process, the proliferation of neuronal progenitors, which do not differentiate into matured neuronal structures, leads to nervous system neoplasm. Products, which would be capable of inducing neurite outgrowth from such progenic cells, would bring a therapeutic and/or preventive and/or palliative solution to such neoplasms.
It has been described that the pathogenicity of a rabies virus strain is inversely correlated with its ability to induce apoptosis (WO 03/048198; Ugolini 1995; Sarmento et al. 2005; Ugolini 2008; Jackson et al. 2008). Therefore, the more virulent a rabies virus strain is, the less apoptotic. The findings that virulent rabies virus strains, such as CVS strains, do not induce neuron apoptosis and explain why virulent rabies virus strains can propagate so extensively within the CNS before the appearance of signs and symptoms of the disease
More recently, Préhaud et al. (2010) reported that the C-terminal region of the cytoplasmic domain of the G protein of rabies viruses is involved in the binding of the G protein to the PDZ domain of the human microtubule associated serine threonine kinase 2 MAST2 protein. This C-terminal region bears a four amino-acid motif called PDZ-BS (PDZ binding site) which has the sequence QTRL in virulent rabies strains and the sequence ETRL in attenuated strains. Thus, the G protein of virulent rabies virus strain has been shown to bind with a high affinity to MAST-1 and MAST-2 but to not bind PTPN4, DLG2 and MPDZ. In contrast, the G protein of attenuated rabies virus strain has been shown to bind with MAST-1, MAST-2, PTPN4, DLG2 and MPDZ. This difference regarding the binding partners of the G protein of virulent and attenuated rabies virus strains seems to be correlated with the difference of virulence of these strains (FIG. 2).
Thus, as demonstrated in application WO2010/116258, the nature of the amino acid residues at positions 491(H/L) and 521(Q/E) of the G protein of rabies viruses is important for the effects on neuron survival and on neurite outgrowth. The G protein of a virulent rabies virus strain presenting a H residue at position 491 and a Q residue at position 521 is non-apoptotic and favours neurite outgrowth. In contrast, the G protein of an attenuated rabies virus strain presenting a L residue at position 491 and a E residue at position 521 is apoptotic and does not promote neurite outgrowth.
Based on these results, there is a need in the art to identify and to design means having improved properties in the promotion of neurite outgrowth and in neurosurvival. The invention provides means for the regeneration and protection of neurons, which derive from the G protein of rabies virus strains, and which show unexpected properties. The invention also concerns means for the screening of molecules suitable for the regeneration and protection of neurons.